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Given annually to a graduate student (or, in this case, a pair of students) working under the supervision of a researcher at Perimeter, the award is named in honour of one of Perimeter's first postdoctoral researchers. Caetano and Toledo won it for their paper, "χ Systems for Correlation Functions."
Caetano and Toledo are supervised by Perimeter Faculty member Pedro Vieira. "The Brodie Prize is meant to reward brilliance, but also independence, and this work is a perfect example that combines both," Vieira says. "Jon and João's paper is an important paper in the field. It would be a significant paper for someone at any stage of their career, but it's particularly impressive as a paper written by students – as a first paper written without supervision."
The work which won Caetano and Toledo the prize started when the pair attended the "Integrability in Gauge and String Theory" conference at Perimeter last year. They saw a talk on correlation functions for three operators in strongly-coupled quantum field theories, and decided to extend it to correlation functions for four operators.
A bit of background: Quantum field theory is a framework for understanding physical particles and their interactions by modelling those particles in terms of an underlying field – rather like understanding the movement of the knots in a fishing net by understanding the net itself. It's a highly successful system that underpins most of modern physics.
Caetano and Toledo are specifically interested in a quantum field theory called N=4 supersymmetric Yang-Mills, which is interesting to physicists because one can in principle solve it exactly. Correlation functions are one of the most interesting things to study within this theory because if you can solve all the correlation functions, you in principle know all the physical information about the theory. Caetano and Toledo were trying to extend a system for understanding the correlations between three operators into a system for understanding the correlations between four operators. They ended up with a system that should work for any number of operators.
Toledo and Caetano at first thought their project would be easy – so easy that Toledo thought they might solve it in one day. "On the face of it," says Caetano, "there was no reason that the same kind of techniques that worked for three points shouldn't work for four." But they didn't.
Their supervisor, Vieira, also thought it might be easy. "When they started, I told them this could be solved trivially, using the same kind of techniques we often use – namely, I thought we could just hit the problem with determinant identities until the problem was dead. I was wrong."
"It was necessary to find a more powerful mathematical technology to solve this problem," Vieira continues. "Namely, João and Jon had to delve into some very advanced papers, such as one from Davide [Perimeter Faculty member Davide Gaiotto] on wall-crossings. They studied these works, and managed to learn this technology, to review it, to simplify it, and to apply it very successfully."
"Yes, there turned out to be a big difference between three points and four points," says Toledo. "The good news is that now that it's done, it should work for any number of points."
"This result is just a beginning," says Vieira. "As you stare at this result, it is so beautiful, and its physics are begging to be interpreted and understood, to be explored further. I think this result is like an island from which these students can explore, and I am sure that they will do that very successfully."
This award honours John Brodie, one of Perimeter's first postdoctoral researchers. Brodie joined the fledgling Perimeter Institute in 2001, having obtained his doctorate in theoretical physics from Princeton University and done postdoctoral work at the Stanford Linear Accelerator Center. During his short career, he published 15 research papers, many of which have proven to be quite influential. His work was notable for its breadth, ranging from nonperturbative effects in supersymmetric gauge theories to string theoretic descriptions of quantum Hall fluids and of inflationary cosmology. Brodie, tragically, died in 2006. He was just 36 years old.


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Southern Baptists Accepting Candidate Nominations for New ERLC President
On Monday, the Ethics and Religious Liberty Commission of the Southern Baptist Convention began accepting candidate nominations for its new commission president as it prepares for the retirement of long-time president Richard Land next fall.
Land has served as the president of the organization for several decades, but in July he announced his plans to retire on Oct. 23, 2013 – his 25th anniversary with the ERLC. Within a month of the announcement the organization had assembled a committee, led by chairman Barry Creamer, to find Land's replacement.
"He has been widely recognized as one of the leading public voices among evangelicals during his presidency. While there is no other Dr. Richard Land, there will be a next president of the ERLC, and needless to say, the expectations for that person are extremely high," said Creamer, who serves as the vice president of academic affairs at Criswell College in Dallas, Texas, on the ERLC website.
The responsibilities of the ERLC president include serving as the organization's CEO, working to promote biblical ethics within the church and among its leaders, promoting religious liberty and more.
The committee is encouraging those who are interested in the position, and those who know someone whom they feel is qualified, to pray about whether or not they should start the candidacy process. They have also made it clear that the person with the most impressive resume will not necessarily become the next president, because they are "pursuing God's will" to make sure the right person is chosen.
The organization released a profile of the type of person they are looking for, however, and they say it is "not likely" they will compromise on any of the characteristics in the profile. These characteristics include faithfulness to the Baptist Faith and Message, understanding of the Bible, ethics, philosophy, theology and history, strong communication skills and leadership experience, among other things.
They also hope to find someone "who is characterized by the qualifications found in 1 Timothy 3," a passage of Scripture that describes an overseer as having characteristics like being "above reproach," "self-controlled," "gentle," "not a lover of money" and able to manage his home and family well.
ERLC is now accepting Curriculum Vitae's from those who believe they should be considered a candidate. Candidate CV's will be accepted until Oct. 31.
The Presidential Search Committee has also created a "Presidential Prayer Guide" for those who want to help by praying that the right candidate would be chosen. All of the suggested prayers on the list are aimed toward the seven committee members, as they are encouraging individuals to pray for their personal spiritual health and for godly wisdom in their search for the next ERLC president.
Once the search committee finds who they believe is the best candidate for the job, they will submit their recommendation to the ERLC board.
Land, who serves as executive editor for The Christian Post, told CP in August that he is retiring from ERLC but not from ministry. He plans to continue addressing important cultural and ethical issues through the Richard Land Center for Cultural Engagement at Southwestern Baptist Theological Seminary.
"I have no intention of retiring from the issues that are of importance to our society," Land told CP. "I feel called to fight for the biblical principles important to our nation and our world."

subset: commoncrawl


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New Marlborough Storytime
January 15 @ 10:00 am - 11:30 am
|Recurring Event (See all)
An event every week that begins at 10:00 am on Wednesday, repeating until May 27, 2020
New Marlborough Library Storytime with Jess
Children and caregivers enjoy a semi-structured group in a rich library environment. Children explore simple toys and puzzles, choose from many books to read, simple crafts and circle/story time.
This is a South Berkshire kids sponsored playgroup.


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Here's one of those perfect dal-and-subzi combinations that's fool-proof and easy to put together, especially on harried weeknights. But before I tell you any more, here's some news: Holy Cow! has a new home: holycowvegan.net. You can continue to catch her at the old url for a while, after which I believe Blogger will forward all visitors to the new address. This should be a seamless transition and hopefully one without any inconvenience to my subscribers.
On to today's recipes, Pancharatan Dal is an Indian classic and the Acorn Squash-Potato Subzi is my own invention. But they go so well together, you'd think it was a match made in food heaven.
Pancharatan translates to five jewels in Hindi, and the jewels here are those tiny, precious nuggets bursting with healthy goodness: lentils. You will usually find a variety of lentils in the Indian pantry but the five in this recipe are the ones most commonly used: Chana dal, Udad Dal, Tuvar Dal, Moong Dal and Masoor Dal.
Each of these lentils has a distinct flavor and texture that stands apart from the rest. Chana Dal is yellow, more rounded, and rather neutral-tasting which is why it is also often used to make traditional Indian sweets. Udad is tiny, with a white center covered by a black skin, and it turns smooth and slippery when cooked. Tuvar is a robust, flavorful lentil that is perhaps the base of most dal recipes. Moong is yellow and tiny and holds its texture better than most lentils. And finally Masoor, a tiny pink lentil and one of my favorites, has an earthy flavor that goes beautifully with meaty vegetables like eggplant and mushrooms.
Imagine the explosion of tastes when all these wonderful dals come together and marry a few magical spices!
As for the subzi, I had some acorn squash lying around for longer than I care to remember or admit, and I decided to add some potatoes into the mix for some texture and flavor and because I honestly believe there is no dish that potatoes cannot improve.
So here are the recipes, and stay tuned after to read my notes on plagiarism, that scourge that seems to afflict every honest blogger these days.
Panchratan Dal
- 1/4 cup chana dal (bengal gram dal)
- 1/4 cup tuvar dal (yellow split peas)
- 1/4 cup udad dal (black gram dal)
- 1/4 cup moong dal
- 1/4 cup masoor dal
- 2 bay leaves
- 1/2 tsp turmeric powder
- 1 tsp mustard seeds
- 1 tsp cumin powder
- 1/2 tsp cardamom powder
- 1 tsp garam masala powder
- 1 tsp red chilli powder , like cayenne or -- if you want it hotter-- paprika
- 1 tbsp grated ginger
- Salt to taste
- Place the dals, bay leaves and turmeric in a pressure cooker or in a pot covered by at least two inches of water
- Bring to a boil and lower the heat, then simmer for about 1/2 an hour or until the lentils have turned really soft. Add more water if needed. Cooking lentils and beans is really easy if you have a pressure cooker which takes much less time as well.
- Heat 1 tbsp oil
- Add the mustard seeds and when they crackle, add the cumin powder, cardamom powder, garam masala, red chili powder and grated ginger. Saute very quickly for about 10 seconds.
- Once the mixture is toasted (not burned), pour into the cooked dal. Add water if the dal is too thick and bring to a boil, then turn down to a simmer. Cook for five minutes.
- Add 1 tablespoon of vegan butter (optional, but does really add a creamy note) and salt to taste.
- Serve hot with boiled rice and subzi
Gingery Acorn Squash And Potato Curry
- 1 acorn squash , peeled and cubed into 1/2-inch pieces
- 2 medium potatoes , cubed and zapped in the microwave with a couple of tablespoons of water for five minutes
- 1 tsp canola or other vegetable oil
- 1 tsp mustard seeds
- 12-15 curry leaves
- 2 tbsp grated ginger
- 2 dry red chillies
- 1 medium onion , diced
- 1/2 tsp turmeric
- Heat the oil. Add the mustard seeds and when they pop add the onions, curry leaves and red chillies.
- Saute until the onions turn translucent. Now add the turmeric and ginger and saute for another minute.
- Add the cubed acorn squash, stir to coat with the spices, then add 1/2 cup of water. Bring to a boil, then lower the heat to a simmer, cover with a lid and let it cook about 7-10 minutes or until the squash is fork-tender.
- Add the cooked, cubed potatoes and stir well together. Add salt to taste.
- Garnish with some mint or some coriander, if desired.
- Serve hot.
A blogger friend recently wrote about plagiarism, and her post moved me enough to want to add my voice. Plagiarism affects nearly every food blogger out there: there are people who will blatantly lift photographs, steal copy, and set up "blog aggregators" that will divert your traffic to their sites.
But what also worries me is the theft of ideas. There are apparently people out there who have no qualms about tweaking someone else's recipe just a little and then passing it off as their own-- something that has happened only too often with my Vegan Whole Wheat Challah Bread and my Mango Bread, among other recipes.
For all those out there who think it's okay to steal ideas and photographs because the anonymity of the Internet somehow makes it okay, be warned that it is not. Giving credit to fellow bloggers and cookbook authors when we use their recipes is not just the right thing to do, it is the only thing to do.


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Anaphase is an extremely important part of cell division yet is only around 1% of the cell cycle length. Anaphase differs slightly in meiosis and mitosis however the overall function remains the same. This part of cell division commences with the Metaphase to Anaphase transition (MAT) where by the Anaphase Promoting Complex/Cyclosome (APC/C) marks the inhibitory protein securin which inhibits the chromatids from early separation. The spindle fibres attach to the centromere of the chromosome and pull them apart to opposite ends of the poles (in mitosis and meiosis II) or pulls each whole chromosome to opposite ends of the poles in meiosis I. The spindle fibres which are not attached to the centromeres exert force against each other and cause the cell to be pushed into an oval shape.
Meiosis versus mitosis
Anaphase in meiosis
meiosis I
- Spindle fibres (attached to the chromatids in metaphase I) pull the two chromosomes apart and move them towards the opposite end of the poles.
- Note that in this stage, the sister chromatids are attached at the centromere.
meiosis II
- The spindle fibres attach to the chromatids and pull each chromatid to opposite ends of the pole.
Anaphase in mitosis
- Segregation of sister chromatids
- Sister chromatids move towards respective poles of the cell, driven by spindle action
- At the end of anaphase, each pole of the cell will have a complete set of chromosomes.
History of Anaphase
|Alexander Kowalevski was the first to comprehend and then figure out the achromatic spindle function.[1]
|Walter Flemming discovered the longitudinal splitting of chromosomes when in mitosis.[2]
|Edmund Beecher Wilson published a timeless work in a book titled "The Cell in Development and Heredity". This book compares the different stages of the cell mitotic cycle and identifies this division process within different organisms specifically contributing to anaphase understanding. [3]
|Hans Ris Uniquely used live imaging as opposed to photographs and identified two stages in anaphase firstly the shrinking as the chromosomes approach the poles and then the elongating as they move further apart.[4]
Extended History
The table above gives key points specific to Anaphase History however critical to Anaphase development a pathway of achievements where made by many scholars, please click on the thumbnail picture below to the right for various websites which contain a wealthy amount of useful chronological information.
Metaphase to anaphase transition (MAT)
Metaphase-to-anaphase transition is tightly controlled by anaphase-promoting complex (APC) motions. APC promotes the degradation of several proteins that inhibit anaphase.[1] The regulatory protein Cdc20 triggers APC/C at the start of the metaphase-anaphase transition. Cdh1 a membrane protein which is able to control the fate of certain cells along with triggering anaphase through the G1 stage of the cell cycle. APC/C specifically targets securin(anaphase inhibitor), Early destruction of this inhibitor is coordinated by nuclear transport factors(Nup98 and Rae1), This mechanism is strictly governed to guarantee appropriate timing of degradation. [2] Mistakes during this process can cause segregation problems leading to the possible demise of the organism. [5]
Process of sister chromatid separation
Sister chromatid separation during anaphase is considered one of the main process of cell division. The chromatids follow a similar path of separation in both meiosis and mitosis. The force of the spindle within the cell stretches the chromatids substantially without detaching which indicates they are physically unable to separate at that point in time. In order for the chromatids to be joined or cohesed together originally, the protein cohesin is employed with the sub units differing between species. Without the cohesion of the chromatids they would be able to separate in any stage of mitosis or meiosis, however the timing of separation is critical for the ultimate survival and correct progression of the cell and organism.
Cohesin binds along various points on the arms of the chromosome (this is dissolutioned during prophase) as well as the centromeric region (the part of the chromosome which includes the centromeric DNA and corresponding proteins [3]. When chromatid segregation occurs, the cohesin protein must therefore be removed to ensure the correct chromatids are segregated to their poles by the spindle fibres. The sororin protein is considered to be one of the main controllers of the sister chromatid separation[4]. It regulates the cohesion of the chromatids by stabilising the cohesin protein to the sister chromatids. Securin, which is involved in the metaphase-anaphase transition, breaks down the cohesin between the two chromatids [5].
In mitosis, the separation of the cohesin is dependent upon the protein separin which is thought to be situated at the mitotic spindle, in the cytoplasm as well as the nucleus. In turn, separin is inhibited by securin (allowing the cohesin to remain intact for that time) and it is then ubiquinated (destroyed by ubiquitin) and separin is able to uncleave the cohesin [6]. Separin has been found to cleave the Scc1/Med1 component of cohesin however the way in which this occurs is currently unknown. Once the cohesin has been cleaved, the sister chromatids are able to be pulled towards the different poles by the spindle fibres [7].
Anaphase to Telophase
Essentially the transition from Anaphase to telophase can take 2 pathways, the conventional or normal pathway involves the co-ordination of Kinetochore and microtubules attachment with the strict dictation from the spindle assembly checkpoint (SAC) where as the other route is basically a "short cut" by passing this checkpoint through a process known as mitotic slippage. The kinetochore is a specific zone located on the chromosomes centromeres. [8] During Anaphase chromatids are pulled apart by the microtubules attached to the kinetochore in the direction of the opposite poles. The organisation of these microtubules is critical for regulation of this phase. [9] Anaphase is defined by the the chromatids separating to become a daughter chromosomes. [10] The SAC is solely responsible for the inhibition of telophase initiation. This checkpoint acts as a government arresting cell processes if there is inadequate supply of kinetochore-microtubule attachments. [11]It should be noted that there are cellular processes that can override and bypass this government through mitotic slippage allowing anaphase lateral entry into telophase. [12]
Spindle Fibers
Spindle fibers in meiosis are known as the meiotic spindle fibers whereas in mitosis mitotic spindle fibers. Spindle fibers are predominantly made up of microtubules, which are mediated by kinetochore. Kinetochore is a complex protein structure that can be found in the chromosomes that link the chromosomes to the spindle microtubules. [13]
Microtubules can be divided into two categories. Microtubules that interact directly with the kinetochores are known as the kinetochore microtubules (kMTs), whereas microtubules that do not interact with the kinetochores directly, instead they interact with the chromosome arm and other microtubules are known as the non-kinetochore microtubules (non-kMTs). In meiosis, the spindle apparatus are mainly made up of non-kinetochore microtubules. The functions of non-kMTs in meiotic spindles are to maintain a stable chromosome positioning, and to form a proper spindle size. Non-kMTs also play a role in the normal dynamics of kMTs. [14]
Chromosome separation occur in 2 phases after metaphase-anaphase transition: [15]
- Anaphase A
- During this phase, chromosomes move toward spindle poles
- This requires the shortening of the chromosome-to-pole microtubules
- Anaphase B
- During this phase, the spindle poles separate from each other
- This requires the elongation of the pole-pole microtubules
- Spindle elongation progresses in 2 stages [16]
- Action of bipolar microtubules-based motors helps the overlapping microtubules of the metaphase spindle fibers to slide away from each other.
- The elongation of spindle fibers are caused by the coupling the polymerization of the plus-end microtubules to the sliding of the opposite spindle pole microtubules
- After the spindle fibers elongate past the spindle overlap zone, they will break into two halves [17]</pubmed>
Microtubules stabilization during spindle elongation needs the opposite activities of Stu2 and Kip3 proteins: [18]
- Stu2: promotes spindle elongation during anaphase
- Kip3: destabilizes the microtubules [19]
Kinetochore is a proteinaceous structure that gathers at the chromosomal centromere region.[20][21] The functions of kinetochores are to facilitate the physical connection between the chromosomes and the spindle microtubules, and also to ensure accurate chromosome separation during anaphase. [22][23][24] During anaphase, kinetochores that are attached to the spindle microtubules are thought to induce forces on the chromosomes, which causes the chromosomes to move towards the opposite poles. [25][26]
Meiotic cells like oocytes (female egg cells) do not contain centrosomes[27][28]. Kinetochores fibers are not involved in the development of the 1st meiotic spindle or in the meiotic chromosome assembly to the metaphase plate[29]. Instead, the meiotic spindle is gathered around the chromatin through a RanGTP –dependent pathway[30][31]. But, it is discovered that microtubules can self-organize into bipolar spindles when the chromatin in absent through motor-driven processes[32][33]. The drawback of non-kinetochore cell division is that it displays a random monopolar action, which resembles chromosome nondisjunction during the error-prone meiosis[34][35]. Consequently, this may cause the formation of cells with abnormal numbers of chromosomes [36]
Chromosomal motors
Plus-end directed motors
These motors are found at the chromosome arms. They are responsible for the "polar ejection" forces that help in positioning chromosomes at the spindle equator during chromosome congression, and they can also generate forces that help to sustain chromosome movement. [37][38] Kinesin-5 is a motor protein that is present in the spindle fibers, which plays a part in mitosis. Meiotic spindles need kinesin-5 for the separation of the spindle poles. [39]Inhibition of kinesin-5 after spindle fiber formation causes the structure to collapse. Hence, kinesin-5 is required in order to maintain the bipolarity of the meiotic spindles. [40]
Kinesin 13 is a protein that plays an important role in depolarizing the minus-ends microtubules at centrosomes. This protein is capable of travelling in both plus-end and minus-end directions. [41][6]
Minus-end directed motors
Dynein a minus-end directed motor is mostly found in the kinetochores & the spindle poles [42][43]. Spindle-associated dynein aid in the assembling of spindle.[44][45][46] Kinetochore-associated dynein (KD) is needed to stabilize the connection between kinetochores and microtubules by generating tension on the kinetochore. In addition, KD also plays a role in silencing the spindle-assembly checkpoint (SAC)[47] that function is making sure that the chromosome separation prerequisites have been met and thus decides whether to implement or delay the chromosome separation.[48]. Absence or decrease in KD may lead to failure of chromosome congression and reduction in chromosome velocity by ~40% during anaphase, without disturbing the poleward microtubules flux rate. [49]
Molecular aspect of anaphase
Cdk1 gene is from Ser/Thr protein kinase family. This gene assists in cell cycle regulation. The activation of CDK 1 protein leads to the initiation and progression of M-phase [50]. Inactivation of this gene allows the formation of the pre-replicative complexes, which is important for DNA replication [51]. Partial activation of this gene might be required in anaphase during the segregation of the sister chromatids [52].Without the inactivation of Cdk1 gene, chromosomes cannot decondense, nuclear envelopes will not be able to reassemble and cell can't divide [53][54][55]. This gene is inactivate via cyclin proteolysis mechanism[56].
APC/C is activated by binding of cdc20. This protein depends on high Cdk1 activity[57]. In anaphase, APC activity is needed but the APC's role in cyclin proteolysis is not sufficient to justify its role in commencing anaphase. In order to initiate anaphase, it is crucial for at least one other APC substrate (such as securin) to be destroyed[58].
APCCdc20 mechanism [59]
- APCCdc20 activates protease separase via securin degradation. Active separase will then cleaves the cohesion complexes of the sister chromatids. Hence, separates them.
- APCCdc20 also activates separase by initiate cyclin B & other mitotic cyclin degradations. Due to the degradation of cylin, CDK1 is inactivated. This allow protein phosphatases to remove the inhibitory phosphate residues from separase.
- APCCdc20 also initiation kinesin Xkid degradation, which is found on the chromosomes arms. Xkid is a plus-end directed motor microtubules. In the early mitosis, Xkid functions to move chromosome away from spindle poles. Therefore, the degradation of Xkid ensures that the chromatids separates toward spindle poles in anaphase.
Separase is a cysteine protein. It is essential in assisting the segregation of sister chromatids. This protein is activated by the proteolysis of securin that is mediated by APC/C. [60]
Cyclin B & Securin
Cyclin b and securin are both the substrate of APC/C. Both the proteins are stable until the initiation of metaphase. Cyclin b and securin degradation will only commence when all chromosomes have attached to the mitotic spindle. This process is mediated by APC/C. The reason is to ensure that the cohesin from sister chromatids are not dissolved before spindle assembly has been completed. Or else this will lead to the missegregation of the sister chromatids, which will cause the formation of aneuploid daughter cell.[61]
Cohesin connects the sister chromatids together. During the transition of metaphase to anaphase, the separase will cleaved the cohesin between the sister chromatids[62][63], which then cause sister chromatids to separate and move towards opposite spindle poles. In higher eukaryotes, like human, there are two different pathways in removing the cohesin[64]. The first pathway occurs during prophase and prometaphase. This pathway depends on Polo-like kinase mechanism[65][66][67]. During this pathway, majority of the cohesin is removed from chromosomes. The second pathway occurs during anaphase due to a small amount of cohesin remains on the chromosomes until the beginning of the anaphase that is normally found in the centromeric region [68][69]. This pathway occurs when separase is activated via APC-dependent securin proteolysis. It removes the remaining cohesin from the chromosome.
Spindle Assembly Checkpoint (SAC)
Spindle assembly checkpoint is the biochemical pathway delays the proteolysis of securin & cyclin b until all chromosomes are bipolarly attached to the mitotic spindle [70]. A single unattached kinetochore is enough to delay all sister chromatids segregation [71]. This checkpoint is believed to measure the tension produced at kinetochore when both the sister chromatids are attached to the opposite poles.[72] [73] Thus, spindle checkpoint[74] ensures correct kinetochore-microtubule arrangement and attachment, anaphase cannot proceed until all chromosomes are aligned correctly in a bipolar fashion.
If SAC failed to function properly, this may lead to
- Cancer due to the formation of aneuploidy cells, which causes chromosomal instability [7]
- Down syndrome because 21 chromosomes fail to segregate properly during meiosis. [8]
Defects resulting from anaphase malformation
Damage to chromosomes
If the chromosome tips are damaged during anaphase then cytokinesis cannot occur[75] and therefore the cell cannot divide into two daughter cells. The experimental removal of chromosomal tips shows cell division being delayed, the furrow itself being delayed or even regressing from its ready to divide state. In the image on the left these and others can be seen.
Mutations of the APC/C
APC/C mutants of C. elegans demonstrate defects in germline proliferation, the development of the female vulva and male tail and the metaphase to anaphase transition in meiosis I. Therefore irregularities in the APC[76] contribute to physical deformities in this species. More on Metaphase-to-Anaphase (mat) transition abnormalities leading to defects in C. elegans here: [9]
Malfunctioning APC/C
The APC/C has many important roles in the development, function and survival of the nervous system[77]. Incorrect APC/C activity leads to some neurological and psychiatric disorders. Research into the APC/C's role in neurobiology may grant us ways to use the APC/C to manage neurological disorders such as mental retardation and autism to even neurodegenerative disorders.
When the chromosomes do not separate properly in anaphase, referred to as "nondisjunction"; aneuploidy results[78]. This refers to an abnormal number of chromosomes, with a well known one being Down's syndrome in which there are three copies of the 21st chromosome[79]. Down's syndrome is also called Trisomy 21 because it is a trisomic (cells with one extra chromosome, 2n+1) subtype of aneuploidy. Another type of trisomy is Patau syndrome (trisomy 13), which unfortunately kills children when they are only months old due to serious defects in the eyes, brain and circulatory system. Edward's syndrome (trisomy 13) similarly leaves children with only months to live as most of their organs are affected. The above mentioned chromosomal disorders pertain to aneuploidy in autosomes (non sex chromosomes, thus not the X or Y chromosomes which determine sex), however there are disorders which affect the allosomes (sex chromosomes). Klinefelter syndrome in males leads to unusual reproductive organs and sterility, as well as the overdevelopment of certain areas such as breasts which lead to feminine body features. Monosomic cells on the other hand are another subtype in which the cell has a missing chromosome (2n-2), this type is most commonly lethal in humans except for one; Turner's syndrome. In Turner's syndrome, females have only one X chromosome instead of the usual XX, females with this disorder do not mature sexually during puberty and are sterile, shorter and of average intelligence.
More on chromosomes here: [10] and human chromosomal disorders here: [11]
Anaphase bridges can cause mutations such as the structural rearrangement of chromosomes which usually lead to the formation of isochromosomes and whole-arm translocations, the loss of the entire chromosome through mitotic spindle detachment or faulty cytokinesis in which the failure to divide results in polyploidy (more than 2 copies of a chromosome) and additional centrosomes which may lead to multipolar spindle formations in future mitosis[80]. The presence of chromatin bridges in Anaphase is also linked to chromosomal instability[81] and cancer.
Anaphase bridges
Centrosomes are specialized structures which mediate chromosome segregation during mitosis. Centromeric ultrafine anaphase bridges are organizations of unresolved DNA strings or catenations between the separating centromeres during anaphase. A study[82] has sought to understand how these bridges disassemble prior to anaphase onset, taking advantage of BLM and PICH helicases, proteins which aid in the colocalization of ultrafine anaphase bridges and promote their disassembly. As PICH is present at centromeres and easily visualized, an extensive range of microscopy techniques were employed in hopes of proving that BLM might also be present at centromeres and that both worked together to resolve DNA catenations before anaphase. It was found that cells which lacked BLM and PICH exhibited changes in their centromere structure, as well as higher rates of centromeric non-disjunction in cells which had no cohesin hinting at catenations which failed to separate. Results showed a relationship between BLM and PICH were important for complete and correct centromere disjunction and a model was proposed which demonstrated the combined effects of BLM and PICH in promoting the organization of centromeric chromatin allowing for the catenates to be easily reached by Topoisomerase IIa, a class of proteins which cut DNA strands in order to manage tangles and unwanted extra coils. This research has contributed to our understanding on how and why sufferers of Bloom's syndrome are more predisposed to cancer.
Current research
Correct division of cellular contents between two daughter cells depends upon spatial and temporal cues; anaphases' microtubular system organizes itself at the spindle midzone and functions to orient the cell division plane in the center of the segregating chromosomes. The signalling pathway responsible for this is not understood, but this molecular study[83] explores how the phosphorylation of Aurora B kinase; a regulator of mitosis, ultimately leads to a gradient which centers at the spindle midzone. The study is therefore successful in the discovery of a possible regulatory mechanism for the anaphase phosphorylation gradient, and suggests that its findings may be useful in the future development of a model for anaphases' spatial patterning.
The Anaphase Promoting Complex/Cyclosome or APC/C moderates mitosis by adding ubiquitin chains to cell cycle regulators, to initiate the formation of these chains the APC/C binds ubiquitin to lysine in substrates and elongates chains via lysine residue modification in attached ubiquitin moieties. How the APC/C and ubiquitin ligases are able to change from lysine residues present on substrates to specific ones on ubiquitin is not known, however; recently the method of assembly for the ubiquitin chains that control the APC/C has been determined. It has been found that by the assembly of certain ubiquitin chains the APC/C initiates substrate degradation, a study[84] has hypothesised that via the APC/C's ability to identify patterns in substrates and ubiquitin allows it to build ubiquitin chains that are able to tightly regulate the cell cycle.
Kinetochores are important structures whose role it is to connect the segregating chromosomes to the spindle microtubules during mitosis. How the meiotic spindle creates the poleward forces to allow for double mitosis resulting in haploid chromosomes is not completely understood, however this study[85] explores how since the DNA beads formed are able to promote the formation of a bipolar spindle they had no need for kinetochores. Dynein, a motor protein which allows for transport of cellular cargo, was thought to have been the culprit. However even after this protein was located and its function ceased, it was noticed that the DNA beads no longer moved towards the poles, but the chromosomes still did. This suggested the possibility of dynein-dependant and dynein-independent poleward movement mechanisms, with the dynein-independent possibly being reliant on the kinetochores.
A recent study[86] investigating the origins of the wait-anaphase signal has concluded that there may be more than one mechanism however they are not fully understood. The researchers have proposed that when the Ndc80 nears Aurora B, it produces unbound kinetochores through the reduction of their affinity to bind to microtubules. The other proposed mechanism is via a conformational change in the Mis12 complex which may move the Ndc80 complex closer to KNL-1 within the KMN network such that it catalyzes the assembly of the MCC.
The Anaphase Catastrophe is a programmed cellular death mechanism (apoptotic) that targets tumour cells that have more than two centrosomes. Tumour cells are able to live with their abnormal number of centrosomes due to a clustering of their centrosomes thanks to special pathways, which allow them to keep the bipolar chromosome segregation seen in normal division. These abnormal cells can then proceed to anaphase with their multipolar spindles and segregate their chromosomes to an unusual number of daughter cells (more than two). All resulting daughter cells will subsequently die; hence this is what is known as anaphase catastrophe. Because it is an intrinsic targeting system for tumour cells, it has been suggested that it may be a target for cancer therapy[87] and warrants further future research. The anaphase catastrophe has demonstrated this ability to interrupt and inhibit the growth and development of malignant cells in this study on lung cancer growth [12]
Earlier this month a study[88] was conducted focusing on APC/C regulation in mammalian meiosis I.
Suggested research
Contractile forces
It has been known for quite some time that due to the extension of the anaphase spindle, spherical tissue cultured cells will elongate to a capsular shape while preparing for cytokinesis. A study[89] has based itself on further understanding the process of anaphase cell elongation, however it is noted that the functions of equatorial contraction, polar relaxation, and the spindle pushing force remain unknown. Whether cell elongation is a phase in its own right or part of another, and how these cellular processes are controlled are not understood.
APC structure & purpose of mitotic phosphorylation
So far, there have not been any successful vertebrate Anaphase Promoting Complex/Cyclosome (APC/C) reconstitutions from recombinant subunits[90] in vitro and thus the purpose of the multiple mitotic phosphorylations it undergoes as well as what kinases are involved remains a target for study. Current study is therefore limited to APC phosphorylation in vitro in comparison with APC modification in vivo, advances have however been made in the effects of regulation via phosphorylation of CDC20, which is a protein complex associated with the APC which serves to activate it.
Anaphase inhibitors as DNA integrity checkpoints during cell division
Research conducted on Saccharomyces cerevisiae (a yeast species) has shown that it is damage induced to the DNA, and not the suppression of DNA replication which leads to the phosphorylation of securin Pds1p; an anaphase inhibitor which prevents anaphase from progressing. This study[91] notes the importance of this in terms of cell division, and suggests its possibility of being a DNA damage checkpoint in mitosis.
Further reading
- Importance of Anaphase in living replicating organisms[92]
- Differences between meiosis and mitosis [13]
- More on anaphase defects [14]
- Mutations in subunits of the APC/C [15]
- Anaphse spindle and its role in the prevention of chromosomal mis-segregation [16]
- Kinetochores, spindles and cell death [17]
- Cancer Treatment research with mitotic focus, specificaaly mitotic slippage [18]
- Breast cancer research with focus on downregulation of the anaphase-promoting complex [19]
- Anaphase Promoting Complex/ Cyclosome (APC/C) - A large protein complex of multiple subunits which activates during cell division and whose purpose it is to signal for anaphase to begin.
- Cyclin-dependent kinase 1 (Cdk 1) - A highly conserved protein that functions as a serine/threonine kinase, , and plays an important role in cell cycle.
- Cell cycle - The series of events that occur within a cell during its lifetime; divided into phases of growth, replication and division into daughter cells.
- Chromosome - Strands of DNA (circular in bacteria, threadlike in eukaryotes) and associated proteins, found in the nuclei of cells and carrier genetic information. Composed of chromatids.
- Chromatin bridge/anaphase bridge - Form when the telomeres of sister chromatids fuse together and do not segregate properly during the anaphase of mitosis.
- Chromatids - The two strands which make up the chromosome, each one contains a double helix of DNA.
- Chromosome centromere - blah
- Cytokinesis - The final stage of cell division in both meiosis and mitosis, wherein the cytoplasm of a dividing cell is constricted so that the cell may separate into the products of cellular division, the daughter cells.
- Isochromosomes - Chromosomes which, after losing one of their arms are replaced with a copy of another arm
- Kinetochores - Chromosomal attachment points (near the centromere) to which bind spindle fibres during cell division.
- KMN network: - Along with the more recently discovered Ska complex (consisting of Ska 1-3 subunits) oversee microtubule (MT) attachment to kinetochores (KT), and are thus crucial to proper mitotic division. The KMN is named according to the first letters in KNL1[20], Mis12[21], and Ndc80[22], which are proteins that assist in cell division and constitute the KMN network.
- Meiosis - One of the two types of cellular division, a reductive type in which the daughter cells, also known as gametes (in males they are sperm cells and in females they are egg cells) are produced. The daughter cells have half the number of chromosomes of the parent cell and are thus termed haploid. Meiosis can be likened to a sort of double mitosis, with the phases being: Interphase, Prophase I, Metaphase I, Anaphase I, Telophase I, Prophase II, Metaphase II, Anaphase II and Telophase II. Four sperm/egg cells are produced which are genetically different to their parent cell with each successful meiotic division, when these cells fuse during sexual reproduction an embryo is created and later develops into a new organism. Oskar Hertwig, a German zoologist, first observed the importance of gametes. [23]
- Microtubule - Part of the eukaryotic cytoskeleton, are hollow rods which serve to support the cytoplasm of a cell thereby maintaining a cell's shape, and in intracellular transport.
- Mitosis - The other type of cell division, all other cells that are not gametes (somatic cells) undergo mitosis in order to replicate. Cells in the human body replicate in order to reproduce resulting in growth or to repair damaged tissues. Mitosis results in two daughter cells that are genetically identical to the parent cell. No crossing over occurs and the daughter cells are diploid, meaning that they have the exact same number of chromosomes as the parent cell. Daughter cells are therefore essentially clones as the parent cell simply replicates its genetic material and splits into two cells.
- Nondisjunction - The process where sister chromatids (mitosis) or homologous chromosome (meiosis) failed to separate during mitosis or meiosis.
- Telomeres: - Located at the ends of each chromatid, they are regions which consist of repeating nucleotide sequences. Their main role is to prevent degradation of the DNA during cell division, and shorten with every division thus acting as a method of preventing unlimited cell proliferation and thus limiting the number of times a cell can divide. There is some very interesting research going on, suggesting that hypothetically, lengthening telomeres would allow humans to live longer. More on the "Hayflick limit", which is the name given to this limited cell division and cell ageing here: http://67-20-95-176.bluehost.com/Hayflick.NatureNotImmortal.pdf
- Phosphorylation - The attachment of a phosphate (PO4) group to a protein or other organic molecule. Usually catalyzed by proteins, the phosphorylation and dephosphorylation (the removal of a PO4 group) usually activate or deactivate the proteins or molecules they're bound to.
- ↑ <pubmed>9425344</pubmed>
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- ↑ <pubmed>9356457</pubmed>
- ↑ <pubmed>19706424</pubmed>
- ↑ <pubmed>11309422</pubmed>
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2013 Projects: Group 1 | Group 2 | Group 3 | Group 4 | Group 5 | Group 6 | Group 7
- Dr Mark Hill 2013, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G


text:
Stanford Health Care today announced its new iOS 8 MyHealth mobile health app for patients. Developed in-house by Stanford Health Care (SHC) engineers, MyHealth connects directly with Epic's EHR, Apple's HealthKit and cloud services for consumer health data monitoring.
The SHC MyHealth mobile app is designed to make it quick and simple for patients to manage their care right from their iPhones, including:
• Make appointments
• Get test results – your lab results are automatically made available in the palm of your hand
• Communicate with your care team through a secure messaging system where your information is always kept confidential
• Have a video visit with your doctor through the new ClickWell Care clinic which gives you the convenient option of a "virtual" appointment
• Manage your prescriptions and medications
• View your health summary
• Access and pay your bills
• Share your vitals with your doctor via HealthKit integration
Secure Messaging
With the new MyHealth app, patients can communicate directly with their care team through a confidential and secure messaging system. In addition, the app automatically syncs with wearable and wireless products, allowing patients to take vital signs at home or on the go. That data is automatically and securely added to the patient's chart in Epic for their physician to review remotely.
"The SHC MyHealth app allows patients to connect their lives with their health care," said Pravene Nath, MD, Chief Information Officer, Stanford Health Care. "By integrating with companies like Withings, our physicians have access to meaningful patient data right in Epic, without having to ask the patient come in for an appointment. We believe this is the future of how care will be delivered for many types of chronic conditions."
The free SHC MyHealth app can be downloaded from the Apple App Store. It is available for current Stanford Health Care patients with a MyHealth account. Existing SHC patients that do not have a MyHealth account can sign up at myhealth.stanfordhealthcare.org.
App screenshots courtesy of Stanford Health Care